Abstract Prolonged orthodontic treatment duration may compromise oral-health related quality of life, and is also closely associated with various side effects such as external root resorption, carious lesions and open gingival embrasures. Orthodontic treatment duration is largely decided by the rate of tooth movement, which is chiefly determined by bone remodeling. Bone remodeling is the life-long continuous replacement of the old bone tissue with new bone. Current clinical methods to accelerate tooth movement involve invasive surgical procedures to stimulate bone remodeling. There is a critical need to develop clinically applicable non-surgical methods to enhance bone remodeling and accelerate tooth movement. The long-term goal of the researcher is to develop clinically applicable pharmacological agents to significantly accelerate orthodontic tooth movement through enhancing alveolar bone remodeling. The level of bone remodeling is closely regulated by hormones, cytokines, prostaglandins, and mechanical loading. Preliminary study data demonstrated that the cytokine vascular endothelial growth factor (VEGF)-A significantly increased proliferation, migration and invasion potentials of osteoblastic cells. VEGF-A also increased RANKL/OPG ratio produced by osteoblastic cells, promoting osteoclast formation. Earlier studies demonstrated that local injection of VEGF in mice significantly increased the rate of orthodontic tooth movement, while neutralizing anti-VEGF antibody had the opposite effects. However, the molecular mechanisms are yet to be elucidated. The overall objective of this proposal is to identify the molecular mechanisms used by VEGF-A to enhance bone remodeling and accelerate tooth movement. The specific aims are: 1): Identify the VEGF-A receptor (VEGFR-1 and/or VEGFR-2) and intracellular signaling pathway(s) leading to the increased osteoblast proliferation, migration and invasion, as well as the increased RANKL/OPG ratio by osteoblasts and induction of osteoclast formation in vitro; 2): Examine the effects of local injection of specific agonists and antagonists of VEGFR-1 and/or VEGFR-2 at the buccal alveolar region close to the maxillary first molar on bone remodeling and orthodontic tooth movement in vivo. First, we will use specific agonists and antagonists of VEGFR-1 or VEGFR-2 and the intracellular signaling pathways they induce to study the intracellular signaling pathways induced by VEGF-A leading to effects in osteoblasts. Second, we will study the effects of the specific agonists and antagonists of VEGFR-1 or VEGFR-2 on the rate of orthodontic tooth movement and bone remodeling with local injections of these factors in mice. Health impact: The current application explores a mechanism that paves road for development of therapeutic agents to significantly reduce treatment time and side effects for millions of orthodontic patients, and will enrich our understanding of the molecular mechanisms controlling bone remodeling, which will allow us to design new therapies and therapeutic agents for related clinical applications.